Oligonucleotides with Sugars Other Than Ribo‐ and 2′‐Deoxyribofuranose in the Backbone: the Solution Structures Determined by NMR in the Context of the ‘Etiology of Nucleic Acids’ Project of Albert Eschenmoser

Abstract

1. Introduction. -Etiology of Nucleic Acids. In the words of Albert Eschenmoser, initiator and spiritus rector of this research project carried out at ETH Zürich and at The Scripps Research Institute (USA) over the last two decades, the goal was to explore the potential of organic chemistry to arrive at an understanding of how and why Nature came to choose the specific structure type of the nucleic acids we know today as the molecular basis of genetic function. The specific property to be compared in this work is a given nucleic acid alternatives capacity for informational Watson -Crick nucleobase pairing, the overall criterion for the selection for study of a given system being a structures potential for constitutional self-assembly as compared to that envisaged for the structure of the natural system itself [1]. Initially, and for the majority of actually synthesized and investigated structures, this latter selection criterion was restricted further by concentrating on alternative nucleic acids in which only the sugar units were varied within the basic architecture of the natural nucleic acids, namely a backbone of (cyclic) sugar units linked by phosphodiester bonds and carrying the canonical nucleobases at C(1') of the sugar (Fig. 1). Therefore, the experimental exploration concentrated on nucleic acids with alternative sugar units that were considered as potentially natural in the sense that they should be derivable from an alternative aldose by the same type of chemistry that allows us to derive the structure of RNA from ribose [1]. This self-restraint to chemically and structurally close relatives of RNA narrowed down the structural space to be explored dramatically and allowed avoiding the speculative question of how an alternative informational biopolymer consisting of building blocks that are structurally much more distant from those of RNA might have self-assembled.Since the aim was to select building blocks that would allow formation of informational pairing systems based on Watson -Crick base pairs, linear or helical translational symmetry of the backbone units along each single strand was required for the conformation in the duplex (pairing conformation). The strategy for finding alternate pairing systems was, therefore, identification of sugar-phosphodiester partial structures that would prefer backbone conformations satisfying this symmetry requirement already in the single strand. Such a preorganization of the single strand in the pairing conformation not only leads to a relatively strain-free duplex (lowering the

Solution Structure and Conformational Dynamics of Deoxyxylonucleic Acids (dXNA): An Orthogonal Nucleic Acid Candidate

“…A large positive twist and lower base-pair rise in natural duplexes are the typical hallmarks of compact, righthanded duplexes with predominantly intrastrand base-stacking interactions, [27] in contrast to the extended dXNA duplexes, which show a large base-pair inclination. In the calculated dXNA duplexes, this large base-pair inclination induces a preferential interstrand, zipperlike base-stacking mode because the interstrand diagonal bases are close to the ideal stacking distance of approximately 3.4 in type-1 duplex structures, as shown in Figure 4 d. Previously, sixmembered sugar-modified DNA (homo-DNA) and RNA (p-RNA) analogues [4,10] were found to adopt these quasilinear duplex structures with large inclination and interstrand base-stacking interactions in solution. An acyclic minimal nucleic acid, namely Glycol nucleic acid (GNA), [28] also [45] and values for L-dXNA and I-dXNA are from ref.…”

“…In contrast, research into alternative nucleic acids to understand the chemical etiology of natural DNA/RNA systems has resulted in the synthesis of nucleic acids like threose nucleic acid (TNA) [3,4,7] and peptide nucleic acid (PNA), [8] which efficiently cross pair with natural DNA/RNA, and self-pairing systems like homo-DNA [1,4,9] and pyranosyl-RNA (p-RNA), [1,4,10] which have a six-membered sugar in the backbone and very high duplex stability. An orthogonal nucleic acid should have a stable [1] duplex structure with reasonable chemical and enzymatic stability, an inability to cross pair with DNA/RNA, and, Abstract: Orthogonal nucleic acids are chemically modified nucleic acid polymers that are unable to transfer information with natural nucleic acids and thus can be used in synthetic biology to store and transfer genetic information independently.…”

“…The study of alternative information systems [1][2][3][4] might explain the reasons for natures selectivity for these systems and not others. Likewise, it might be important to select alternative nucleic acids to build an orthogonal information system for the safe transfer of genetic information in engineered life forms.…”

“…Keywords: DNA structures · helical structures · NMR spectroscopy · nucleic acids · orthogonal nucleic acids · synthetic biology preferably, a flexible backbone [4,5] to allow the formation of the various secondary and tertiary structures needed for information storage, transfer, and catalysis.…”

Ätiologie potentiell primordialer Biomolekül‐Strukturen: Vom Vitamin B12zu den Nukleinsäuren und der Frage nach der Chemie der Entstehung des Lebens – ein Rückblick

“…Die NMR-spektroskopisch ermittelte Struktur des p-RNA-Duplexes der antiparallel-selbstkomplementären Basensequenz 4'-CGAATTCG ist eine schwach linkshelikale Leiterstruktur mit starker Rückgratneigung. [136,169] Präbiotische Chemie…”